Use of imidazolinone derivatives in combination with radiation therapy in the treatment of tumors - Patents.com

Abstract

The present invention provides the use of a compound represented by general formula (I) in combination with radiation therapy in medicine for treating cancer. [Formula 1] JPEG2025529629000079.jpg4476

Description

[Technical Field]

[0001] The present invention relates to the use of imidazolinone derivatives for the treatment of tumors in combination with radiotherapy. [Background technology]

[0002] Radiation therapy is one of the most important methods for comprehensive treatment of malignant tumors, and neoadjuvant therapy based on traditional long-term radiation therapy has become the standard regimen for treating various malignant tumors.However, long-term clinical trials have found that the response of patients with malignant tumors to radiation therapy varies greatly.Some patients can achieve complete pathological remission at the end of the treatment cycle, but there are still some patients who cannot benefit from long-term treatment, and some patients even experience progression.Research has found that the increase in the repair mechanism of DNA damage caused by radiation therapy is an important reason for the resistance mechanism of tumors to radiation therapy.

[0003] DNA double-strand breaks (DSBs) are a highly harmful form of DNA damage in cells, and untimely repair of DSBs is closely related to cellular carcinogenesis. Non-homologous end joining (NHEJ) is one of the major pathways for DNA double-strand break repair in cells. In NHEJ, DSB ends are first recognized and bound by Ku70 / 80, which then binds to the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form the DNA-dependent protein kinase (DNAPK), or NHEJ initiation complex (DNAPK). Subsequently, two DNAPKs bind to the damaged DNA ends and simultaneously recruit subsequent NHEJ repair factors (XRCC4 and XLF) and DNA ligase IV (LigIV) to repair the damaged DNA. Studies have shown that DNA-PK activity is associated with drug resistance due to radiation therapy, and thus the killing effect of radiation therapy on tumor cells can be improved by inhibiting DNA-PK activity in tumor cells. However, no effective DNA-PK inhibitors have yet been marketed. Therefore, developing potent DNA-PK inhibitors as radiosensitive drugs for tumor treatment has important clinical implications.

[0004] WO2021209055 discloses the use of imidazolinone derivatives in the preparation of drugs for use in the treatment of cancer, where the compounds described therein have high selectivity and significant inhibitory activity against DNA-PK.

[0005] In this specification, the inventors of the present invention aim to increase the sensitivity of tumors to radiation therapy by combining the prior art with radiation therapy to overcome the shortcomings of the prior art. Summary of the Invention

[0006] It is an object of the present invention to provide the use of imidazolinone derivatives for the treatment of tumors in combination with radiation therapy, in order to overcome the deficiencies of the prior art.

[0007] In one or more embodiments of the present application, there is provided the use of a compound of general formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, as an active ingredient for treating tumors in combination with radiation therapy: [ka] (In the formula, [ka] teeth, [ka] and [ka] is a single or double bond, [ka] wherein A, B, C, and D are each independently C or N, and at least one of A, B, C, and D is N; R0 is H, C 1~6 alkyl or cyclopropyl, C 1~6 the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is [ka] or pyridyl, and R1 is D, halogen, cyano, hydroxyl, C 1~6 Alkyl and C 1~6 optionally further substituted with one or two substituents selected from alkoxy; R 1a is H or C 1~6 is alkyl, R 1b is H, OH, cyano or hydroxyl substituted C 1~6 is alkyl, R2 is H, cyano, =O, carboxyl, -C(=O)NR 2a R 2b , C 1~6 Alkoxy, C 1~6 Alkyl, halogen, -S(=O)2R 2a or -C(=O)OC 1~6 alkyl, C 1~6 Alkyl, -C(=O)OC 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium; R 2a and R 2b are independently H, C 1~6 alkyl or 3- to 5-membered cycloalkyl, C 1~6 Alkyl is OH, D, halogen, C 1~6 Alkyl and C 1~6 and optionally further substituted with one or more substituents selected from alkoxy; Alternatively, R 2a and R 2b together with the atoms to which they are attached form a 5-6 membered heterocyclyl, which contains 1, 2 or 3 heteroatoms selected from N, O and S, and C 1~6 optionally further substituted with one or more substituents selected from alkyl, OH and halogen; R3 is halogen or C 1~6 alkyl, C 1~6 the alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1, n is 0, 1 or 2; x and y are each independently 1, 2, or 3; however, [ka] , R0, R2 and R3 simultaneously satisfy the following conditions: [ka] isn't it: [ka] but, [ka] wherein n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl).

[0008] In one or more embodiments of the present application, R1 is [ka] and R 1a is H or C 1~6 is alkyl, R2 is H, cyano, -C(=O)NR 2a R 2b , C 1~6 Alkoxy, halogen, -S(=O)2R 2a or -C(=O)OC 1~6 Alkyl, -C(=O)OC 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium; R 2a and R 2b are independently H, C 1~6 alkyl or 3- to 5-membered cycloalkyl, C 1~6 the alkyl is optionally further substituted with one or more substituents selected from OH, D or halogen; Alternatively, R 2a and R 2b taken together with the atoms to which they are attached form a 5-6 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and optionally further substituted with one or more substituents selected from OH and halogen; R3 is halogen or C 1~6 alkyl, C 1~6 the alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1, n is 0, 1 or 2; however, [ka] , R0, R2 and R3 simultaneously satisfy the following conditions: [ka] isn't it: [ka] but, [ka] wherein n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

[0009] In one or more embodiments of the present application, [ka] teeth, [ka] and R0 is H, C 1~4 alkyl or cyclopropyl, C 1~4 The alkyl is optionally further substituted with one or more substituents selected from halogen and D; R1 is [ka] and R 1a is H, C 1~6 Alkyl or -C(=O)C1~6 is alkyl, R2 is H, cyano, -C(=O)NR 2a R 2b , C 1~6 Alkoxy, halogen, -S(=O)2R 2a or -C(=O)OC 1~6 Alkyl, -C(=O)OC 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium; R 2a and R 2b are independently H, C 1~6 alkyl or 3- to 5-membered cycloalkyl, C 1~6 the alkyl is optionally further substituted with one or more substituents selected from OH, D and halogen; Alternatively, R 2a and R 2b taken together with the atoms to which they are attached form a 5-6 membered heterocyclyl, which contains 1-3 heteroatoms selected from N, O and S, and which is also optionally further substituted with one or more substituents selected from OH and halogen; R3 is halogen or C 1~6 alkyl, C 1~6 the alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1, n is 0, 1 or 2; however, [ka] , R0, R2 and R3 simultaneously satisfy the following conditions: [ka] isn't it: [ka] but, [ka] When n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

[0010] In one or more embodiments of the present application, there is provided the use of a compound of general formula (II), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, as an active ingredient for treating tumors in combination with radiation therapy: [ka] (In the formula, R0 is H, C 1~6 alkyl or cyclopropyl, C 1~6 the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is [ka] or pyridyl, and R1 is D, halogen, cyano, hydroxyl, C 1~6 Alkyl and C 1~6 optionally further substituted with 1 to 2 substituents selected from alkoxy; R 1a is H or C 1~6 is alkyl, R 1b is H, OH, cyano or hydroxyl substituted C 1~6 is alkyl, R 2c is H, cyano, halogen or C 1~6 is an alkoxy; R 2d is H, cyano, carboxyl, -C(=O)NR 2a R 2b , C 1~6 Alkyl, halogen, -S(=O)2R 2a or -C(=O)OC 1~6alkyl, C 1~6 Alkyl and -C(=O)OC 1~6 the alkyl is optionally substituted with one or more substituents selected from halogen and deuterium; R 2a and R 2b is H, C 1~6 alkyl or 3- to 5-membered cycloalkyl, C 1~6 Alkyl is OH, D, halogen, C 1~6 Alkyl and C 1~6 and optionally further substituted with one or more substituents selected from alkoxy; Alternatively, R 2a and R 2b together with the atoms to which they are attached form a 5-6 membered heterocyclyl, which contains 1-3 heteroatoms selected from N, O and S, and C 1~6 optionally further substituted with one or more substituents selected from alkyl, OH and halogen; R3 is halogen or C 1~6 alkyl, C 1~6 the alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1, n is 0, 1 or 2; x and y are each independently 1, 2, or 3; however, [ka] , R0, R2 and R3 simultaneously satisfy the following conditions: [ka] isn't it: [ka] but, [ka] wherein n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

[0011] In one or more embodiments of the present application, there is provided the use of a compound of general formula (III), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, as an active ingredient for treating tumors in combination with radiation therapy: [ka] (In the formula, R0 is H, C 1~6 alkyl or cyclopropyl, C 1~6 the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is [ka] or pyridyl, and R1 is D, halogen, cyano, hydroxyl, C 1~6 Alkyl and C 1~6 optionally further substituted with 1 to 2 substituents selected from alkoxy; R 1b is H, OH, cyano or hydroxyl substituted C 1~6 is alkyl, R 2a and R 2b are independently H, C 1~6 alkyl or 3- to 5-membered cycloalkyl, C 1~6 the alkyl is optionally further substituted with one or more substituents selected from D or halogen; Alternatively, R 2a and R 2b together with the atoms to which they are attached form a 5-6 membered heterocyclyl, which contains 1-3 heteroatoms selected from N, O and S, and C 1~6optionally further substituted with one or more substituents selected from alkyl, OH and halogen; R 2c is H, cyano, halogen or C 1~6 Alkoxy, C 1~6 the alkoxy is optionally substituted with one or more deuterium atoms; R3 is halogen or C 1~6 alkyl, C 1~6 the alkyl is optionally further substituted with 1 to 3 substituents selected from D or halogen; m is 0 or 1, n is 0, 1 or 2; x and y are each independently 1, 2, or 3.

[0012] In one or more embodiments of the present application, there is provided the use of a compound of general formula (IV), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, as an active ingredient for treating tumors in combination with radiation therapy: [ka] (In the formula, R0 is H, C 1~6 alkyl or cyclopropyl, C 1~6 the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is -(CH) m -4 to 7-membered carbocyclyl, -(CH) m -4 to 7-membered heterocyclyl, -(CH) m -8 to 12-membered bridged ring, -(CH) m -7 to 12-membered spiro ring, -(CH) m -4 to 7-membered carbocyclyl, -(CH) m -4 to 7-membered heterocyclyl, -(CH) m -8 to 12-membered bridged ring or -(CH) m -7 to 12 membered spiro rings are hydroxy, cyano, halogen, ═O, C 1~6Alkyl, C 1~6 Alkoxy and Hydroxy Substituted C 1~6 alkyl).

[0013] In one or more embodiments of the present application, R0 is H, C 1~6 alkyl or cyclopropyl, C 1~6 the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is [ka] or pyridyl, and R1 is D, halogen, cyano, hydroxyl, C 1~6 Alkyl and C 1~6 optionally further substituted with 1 to 2 substituents selected from alkoxy; R 1a is H or C 1~6 is alkyl, R 1b is H, OH, cyano or hydroxyl substituted C 1~6 is alkyl, m is 0 or 1, x and y are each independently 1, 2, or 3.

[0014] In one or more embodiments of the present application, R0 is C 1~4 alkyl, C 1~4 the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is [ka] is.

[0015] In one or more embodiments of the present application, the active ingredient is [ka] [ka] [ka] [ka] is selected from.

[0016] In one or more embodiments of the present application, the active ingredient, when used in combination with radiation therapy, has the effect of increasing the sensitivity of tumors to radiation therapy.

[0017] In one or more embodiments of the present application, the tumor is selected from a solid tumor. [Brief explanation of the drawings]

[0018] [Figure 1] FIG. 1 shows Compound A. [Figure 2] FIG. 1 shows a graph of tumor volume trends in a BALB / c mouse model bearing CT26 transplanted tumors. [Figure 3] FIG. 1 shows a graph of the trend of body weight change in a BALB / c mouse model bearing a CT26 transplanted tumor. DETAILED DESCRIPTION OF THE INVENTION

[0019] The implementation process and beneficial effects of the present invention are described in detail below with examples, which are intended to help the reader better understand the essential matters and features of the present invention, but are not intended to limit the implementation scope of the present invention.

[0020] The invention will be described in further detail below with reference to the accompanying drawings.

[0021] Compound A in this example is Compound 62 of WO 2021209055 and is prepared in accordance with the preparation method thereof.

[0022] Inhibition experiments using a BALB / c mouse model bearing CT26 transplanted tumors 1. Experimental steps: Female BALB / c mice were selected to construct a CT26 subcutaneously implanted tumor model by subcutaneous injection of tumor cells. The average tumor volume was 150-200 mm. 3 Once the mice reached the target age, they were divided into three experimental groups: vehicle, IR, and (Compound A (20 mpk) + IR), each containing 8 animals per group for the grouping experiment, for a total of 24 animals. Each irradiated group received 2 Gy of radiation for 5 consecutive days, the treatment group received the corresponding drug once a day for 39 consecutive days, and the vehicle group received the vehicle.

[0023] 2. Assay Method 2.1 Tumor volume: During the drug treatment cycle, the long diameter (a) and short diameter (b) of the tumor tissue were measured using an electronic Vernier caliper to calculate the tumor volume (tumor volume = 0.5 × a × b 2 ).

[0024] 2.2 Mouse weight: Mice were weighed at least twice a week during the drug treatment cycle.

[0025] 3. Experimental Results 3.1 Tumor volume results

[0026] [Table 1]

[0027] As shown in Table 1 and Figure 2, the tumor volume of the group treated with compound A in combination with IR was significantly reduced compared with that of the vehicle and IR groups, and after 4 days of treatment, the difference in volume between the group treated with compound A in combination with IR and the IR group gradually increased, indicating that compound A can significantly improve the antitumor effect of radiation therapy.

[0028] 3.2 Weight results

[0029] [Table 2]

[0030] As shown in Table 2 and Figure 3, the body weight of the mice in the vehicle group remained stable throughout the experiment. The body weight of the IR group decreased slightly during irradiation and began to increase after irradiation. At the end of the experiment on D39, there was no significant difference in the average body weight between the IR group and the group treated with Compound A in combination with IR, indicating that the treatment of Compound A in combination with radiation therapy did not affect the weight gain of the animals and was well tolerated by the animals.

[0031] Specific embodiments are described in detail in the description of the present invention. Those skilled in the art should realize that the above embodiments are illustrative and cannot be construed as limiting the present invention. In addition, those skilled in the art can make some improvements and modifications to the present invention without departing from the principle of the present invention, and the technical solutions obtained based on these improvements and modifications will still fall within the scope of protection of the claims of the present invention.

Claims

1. Use of a compound of formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, as an active ingredient for the treatment of tumors in combination with radiation therapy: 【Chemical 1】 (In the formula, 【Chemistry 2】 teeth, 【Chemistry 3】 and 【Chemistry 4】 is a single or double bond, 【Chemistry 5】 wherein A, B, C, and D are each independently C or N, and at least one of A, B, C, and D is N; R ０ is H, C １～６ alkyl or cyclopropyl, １～６ the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R １ teeth, 【Chemistry 6】 or pyridyl, and R １ is D, halogen, cyano, hydroxyl, C １～６ Alkyl and C １～６ optionally further substituted with 1 or 2 substituents selected from alkoxy; R １ａ is H or C １～６ is alkyl, R １ｂ is H, OH, cyano or hydroxyl substituted C １～６ is alkyl, R ２ is H, cyano, ═O, carboxyl, —C(═O)NR ２ａ R ２ｂ , C １～６ Alkoxy, C １～６ Alkyl, halogen, -S(=O) ２ R ２ａ or -C(=O)OC １～６ alkyl, １～６ Alkyl, —C(═O)OC １～６ Alkyl or C １～６ The alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium; R ２ａ and R ２ｂ are each independently H, C １～６ alkyl or 3- to 5-membered cycloalkyl, １～６ Alkyl is OH, D, halogen, C １～６ Alkyl and C １～６ optionally further substituted with one or more substituents selected from alkoxy; Alternatively, R ２ａ and R ２ｂ together with the atoms to which they are attached form a 5- to 6-membered heterocyclyl, which contains 1, 2, or 3 heteroatoms selected from N, O, and S, and C １～６ optionally further substituted with one or more substituents selected from alkyl, OH, and halogen; R ３ is a halogen or C １～６ alkyl, １～６ the alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; x and y are each independently 1, 2, or 3; however, 【Chemistry 7】 , R ０ , R ２ and R ３ If the following conditions are satisfied simultaneously, R １ teeth, 【Chemistry 8】 isn't it: 【Chemistry 9】 but, 【Chemistry 10】 where n is 1 and R ０ is H or methyl, and R ２ is methoxy or -S(=O) ２ Me and R ３ is methyl).

2. 2. The use according to claim 1, wherein the active ingredient is a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein: R １ teeth, 【Chemistry 11】 and R １ａ is H or C １～６ is alkyl, R ２ is H, cyano, -C(=O)NR ２ａ R ２ｂ , C １～６ Alkoxy, halogen, -S(=O) ２ R ２ａ or -C(=O)OC １～６ alkyl, and the —C(═O)OC １～６ Alkyl or C １～６ The alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium; R ２ａ and R ２ｂ are each independently H, C １～６ alkyl or 3- to 5-membered cycloalkyl, １～６ the alkyl is optionally further substituted with one or more substituents selected from OH, D or halogen; Alternatively, R ２ａ and R ２ｂ together with the atoms to which they are attached form a 5-6 membered heterocyclyl, which contains 1-3 heteroatoms selected from N, O and S, and is optionally further substituted with one or more substituents selected from OH and halogen; R ３ is a halogen or C １～６ alkyl, １～６ the alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; however, 【Chemistry 12】 , R ０ , R ２ and R ３ If the following conditions are satisfied simultaneously, R １ teeth, 【Chemistry 13】 isn't it: 【Chemistry 14】 but, 【Chemistry 15】 where n is 1 and R ０ is H or methyl, and R ２ is methoxy or -S(=O) ２ Me and R ３ is methyl).

3. 2. The use according to claim 1, wherein the active ingredient is a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein: 【Chemistry 16】 teeth, 【Chemistry 17】 and R ０ is H, C １～４ alkyl or cyclopropyl, １～４ The alkyl is optionally further substituted with one or more substituents selected from halogen and D; R １ teeth, 【Chemistry 18】 and R １ａ is H, C １～６ Alkyl or -C(=O)C １～６ is alkyl, R ２ is H, cyano, -C(=O)NR ２ａ R ２ｂ , C １～６ Alkoxy, halogen, -S(=O) ２ R ２ａ or -C(=O)OC １～６ alkyl, and the —C(═O)OC １～６ Alkyl or C １～６ The alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium; R ２ａ and R ２ｂ are each independently H, C １～６ alkyl or 3- to 5-membered cycloalkyl, １～６ the alkyl is optionally further substituted with one or more substituents selected from OH, D and halogen; Alternatively, R ２ａ and R ２ｂ together with the atoms to which they are attached form a 5-6 membered heterocyclyl, which contains 1-3 heteroatoms selected from N, O and S, and which is also optionally further substituted with one or more substituents selected from OH and halogen; R ３ is a halogen or C １～６ alkyl, １～６ the alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; however, 【Chemistry 19】 , R ０ , R ２ and R ３ If the following conditions are satisfied simultaneously, R １ teeth, 【Chemistry 20】 isn't it: 【Chemical 21】 but, 【Chemical 22】 When n is 1, R ０ is H or methyl, and R ２ is methoxy or -S(=O) ２ Me and R ３ is methyl).

4. 2. The use according to claim 1, wherein the active ingredient is selected from a compound of formula (II) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof: 【Chemical 23】 (In the formula, R ０ is H, C １～６ alkyl or cyclopropyl, １～６ the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R １ teeth, 【Chemistry 24】 or pyridyl, and R １ is D, halogen, cyano, hydroxyl, C １～６ Alkyl and C １～６ optionally further substituted with 1 to 2 substituents selected from alkoxy; R １ａ is H or C １～６ is alkyl, R １ｂ is H, OH, cyano or hydroxyl substituted C １～６ is alkyl, R ２ｃ is H, cyano, halogen or C １～６ is an alkoxy; R ２ｄ is H, cyano, carboxyl, -C(=O)NR ２ａ R ２ｂ , C １～６ Alkyl, halogen, -S(=O) ２ R ２ａ or -C(=O)OC １～６ alkyl, １～６ Alkyl and —C(═O)OC １～６ the alkyl is optionally substituted with one or more substituents selected from halogen and deuterium; R ２ａ and R ２ｂ is H, C １～６ alkyl or 3- to 5-membered cycloalkyl, １～６ Alkyl is OH, D, halogen, C １～６ Alkyl and C １～６ optionally further substituted with one or more substituents selected from alkoxy; Alternatively, R ２ａ and R ２ｂ together with the atoms to which they are attached form a 5-6 membered heterocyclyl, which contains 1-3 heteroatoms selected from N, O and S, and C １～６ optionally further substituted with one or more substituents selected from alkyl, OH, and halogen; R ３ is a halogen or C １～６ alkyl, １～６ the alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; x and y are each independently 1, 2, or 3; however, 【Chemistry 25】 , R ０ , R ２ and R ３ If the following conditions are satisfied simultaneously, R １ teeth, 【Chemical 26】 isn't it: 【Chemical 27】 but, 【Chemical Formula 28】 n is 1; and R ０ is H or methyl, and R ２ is methoxy or -S(=O) ２ Me and R ３ is methyl).

5. 5. The use according to claim 4, wherein the active ingredient is selected from a compound of formula (III) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof: 【Chemical 29】 (In the formula, R ０ is H, C １～６ alkyl or cyclopropyl, １～６ the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R １ teeth, 【Chemistry 30】 or pyridyl, and R １ is D, halogen, cyano, hydroxyl, C １～６ Alkyl and C １～６ optionally further substituted with 1 to 2 substituents selected from alkoxy; R １ｂ is H, OH, cyano or hydroxyl substituted C １～６ is alkyl, R ２ａ and R ２ｂ are each independently H, C １～６ alkyl or 3- to 5-membered cycloalkyl, １～６ The alkyl is optionally further substituted with one or more substituents selected from D or halogen; Alternatively, R ２ａ and R ２ｂ together with the atoms to which they are attached form a 5-6 membered heterocyclyl, which contains 1-3 heteroatoms selected from N, O and S, and C １～６ optionally further substituted with one or more substituents selected from alkyl, OH, and halogen; R ２ｃ is H, cyano, halogen or C １～６ is an alkoxy, １～６ the alkoxy is optionally substituted with one or more deuterium atoms; R ３ is a halogen or C １～６ alkyl, １～６ the alkyl is optionally further substituted with 1 to 3 substituents selected from D or halogen; m is 0 or 1; n is 0, 1 or 2; x and y are each independently 1, 2, or 3.

6. 2. The use according to claim 1, wherein the active ingredient is selected from a compound of formula (IV) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof: 【Chemical 31】 (In the formula, R ０ is H, C １～６ alkyl or cyclopropyl, １～６ the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R １ is -(CH) ｍ -4 to 7-membered carbocyclyl, -(CH) ｍ -4 to 7-membered heterocyclyl, -(CH) ｍ -8 to 12-membered bridged ring, -(CH) ｍ -7 to 12-membered spiro ring, wherein the -(CH) ｍ -4 to 7-membered carbocyclyl, -(CH) ｍ -4 to 7-membered heterocyclyl, -(CH) ｍ -8 to 12-membered bridged ring or -(CH) ｍ - 7 to 12 membered spiro rings are hydroxy, cyano, halogen, ═O, C １～６ Alkyl, C １～６ Alkoxy and hydroxy substituted C １～６ and optionally further substituted with one or more substituents selected from alkyl.

7. the active ingredient is selected from a compound of formula (IV) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof; R ０ But H, C １～６ alkyl or cyclopropyl, １～６ the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R １ but, 【Chemical 32】 or pyridyl, and R １ D, halogen, cyano, hydroxyl, C １～６ Alkyl and C １～６ optionally further substituted with 1 to 2 substituents selected from alkoxy; R １ａ is H or C １～６ is alkyl, R １ｂ is H, OH, cyano or hydroxyl substituted C １～６ is alkyl, m is 0 or 1; x and y are each independently 1, 2, or 3; 7. The use according to claim 6.

8. the active ingredient is a compound of formula (IV) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof; R ０ But C １～４ alkyl, １～４ the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R １ but, 【Chemical 33】 That is, 8. The use according to claim 7.

9. The active ingredient is 【Hua 34-1】 【Chemistry 34-2】 【Hua 34-3】 【Hua 34-4】 【Chemistry 34-5】 The use according to any one of claims 1 to 8, wherein the compound is selected from the group consisting of:

10. The use according to any one of claims 1 to 9, wherein the tumor is selected from solid tumors.

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